Holistic methodologies in the study of Scotland’s early stone castles and landscapes (c.1050-c.1350 CE) with reference to the Earldom of Orkney and the Lordship of Galloway

The historiography of Scottish castles was dominated, until the 1960s, by great works which defined the field for generations of historians and archaeologists. Since then several major excavations, intensive wide-ranging fieldwork and most recently, targeted topographic surveys, have brought a new body of evidence to the discussion. Familiar themes, however, still dominate how castles are understood: the dichotomy between ‘native’ and ‘newcomer’, the debate over function and form, for example. This thesis brings to bear the new body of evidence alongside a specific focus on castles and their landscapes for the period of c.1050-c.1350. It begins, firstly, with an examination of the full body of castle sites and contemporary secular power centres, following the typology-oriented categorisation of sites by RCAHMS (now HES). Included in this are sites in the formal typology of crannogs, brochs and duns, which evidence suggests were occupied for some or all of the period under discussion. The 12th to 13th centuries demonstrated the peak of first phase of castle occupation. There is a resultant impact on what might be expected from landscapes of lordship, borne out in the second section of the thesis, the regional studies. The first regional study examines the evidence for castles in the Earldom of Orkney, which conventional thinking suggests is home to Scotland’s earliest stone castle. Contemporary parallels are established with Norwegian and Swedish castles. Study of the landscape context suggests that the builders of castle sites in the 12th-century Earldom relied not on terrestrial, landed wealth but political authority and kinship with the comital family. Substantial wealth, derived from maritime exploitation, is also likely. The second regional study, of the Lordship of Galloway, looks at the emergence of stone castles there in connection to the political developments within the polity. Landscape assessment hints at a function of castle sites in the Lordship in relation to transhumance practice and fishing. The diversity of architectural expression of lordship is discussed. Study of the place-name context, useful in determining the status of farms or townships, reveals the unparalleled linguistic (and cultural) complexity of south-west Scotland, with resultant impact on underlying structures of local lordship. In the cases of Orkney and Galloway, trends are apparent which argue for the early stone castles of Scotland to be considered within highly contingent personal, political and social terms. Though they represent evidence for larger historical and architectural trends, the most compelling interpretation of these monuments frames their appearance in relation to their builders’ histories, connections, ambitions and preferences. Where physical evidence is lacking for castles, landscapes around known castle sites provide the material to understand lost monuments by their imprint on their surroundings

Numerical Solution of Differential Equations by the Parker-Sochacki Method

A tutorial is presented which demonstrates the theory and usage of the Parker-Sochacki method of numerically solving systems of differential equations. Solutions are demonstrated for the case of projectile motion in air, and for the classical Newtonian N-body problem with mutual gravitational attraction.Comment: Added in July 2010: This tutorial has been posted since 1998 on a university web site, but has now been cited and praised in one or more refereed journals. I am therefore submitting it to the Cornell arXiv so that it may be read in response to its citations. See "Spiking neural network simulation: numerical integration with the Parker-Sochacki method:" J. Comput Neurosci, Robert D. Stewart & Wyeth Bair and http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2717378

Pentraxins coordinate excitatory synapse maturation and circuit integration of parvalbumin interneurons

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.Circuit computation requires precision in the timing, extent, and synchrony of principal cell (PC) firing that is largely enforced by parvalbumin-expressing, fast-spiking interneurons (PVFSIs). To reliably coordinate network activity, PVFSIs exhibit specialized synaptic and membrane properties that promote efficient afferent recruitment such as expression of high-conductance, rapidly gating, GluA4-containing AMPA receptors (AMPARs). We found that PVFSIs upregulate GluA4 during the second postnatal week coincident with increases in the AMPAR clustering proteins NPTX2 and NPTXR. Moreover, GluA4 is dramatically reduced in NPTX2(-/-)/NPTXR(-/-) mice with consequent reductions in PVFSI AMPAR function. Early postnatal NPTX2(-/-)/NPTXR(-/-) mice exhibit delayed circuit maturation with a prolonged critical period permissive for giant depolarizing potentials. Juvenile NPTX2(-/-)/NPTXR(-/-) mice display reduced feedforward inhibition yielding a circuit deficient in rhythmogenesis and prone to epileptiform discharges. Our findings demonstrate an essential role for NPTXs in controlling network dynamics highlighting potential therapeutic targets for disorders with inhibition/excitation imbalances such as schizophrenia.Work supported by a PRAT fellowship to M.S.W., an NICHD intramural award to C.J.M., NIDCD intramural research program funding to R.S.P., an NIMH intramural award to H.A.C., NIH grants (PAR-02-059, NS 039156) to P.F.W., and an NIH grant (EY022730) to M.T.

Effect of promoter architecture on the cell-to-cell variability in gene expression

According to recent experimental evidence, the architecture of a promoter, defined as the number, strength and regulatory role of the operators that control the promoter, plays a major role in determining the level of cell-to-cell variability in gene expression. These quantitative experiments call for a corresponding modeling effort that addresses the question of how changes in promoter architecture affect noise in gene expression in a systematic rather than case-by-case fashion. In this article, we make such a systematic investigation, based on a simple microscopic model of gene regulation that incorporates stochastic effects. In particular, we show how operator strength and operator multiplicity affect this variability. We examine different modes of transcription factor binding to complex promoters (cooperative, independent, simultaneous) and how each of these affects the level of variability in transcription product from cell-to-cell. We propose that direct comparison between in vivo single-cell experiments and theoretical predictions for the moments of the probability distribution of mRNA number per cell can discriminate between different kinetic models of gene regulation.Comment: 35 pages, 6 figures, Submitte

Factors associated with self-reported health among New Zealand military veterans: a cross-sectional study

Objective To identify factors associated with better or poorer self-reported health status in New Zealand military Veterans. Design A cross-sectional survey. Participants The participants of interest were the 3874 currently serving Veterans who had been deployed to a conflict zone, but all Veterans were eligible to participate. Study variables The EQ-5D-5L, asking about problems across five dimensions (mobility, self-care, usual activities, pain or discomfort and anxiety or depression), with five levels of severity (eg, no, slight, moderate, severe or extreme problems), also containing a Visual Analogue Scale (EQ-VAS) to self-assess health state, scaled from 0 (worst) to 100 (best) imagined health. Hypothetical relationships with better health were positive social support, sleep and psychological flexibility; with poorer health, post-traumatic stress, exposure to psychological trauma, distress and hazardous drinking. Results The EQ5-D-5L was completed by 1767 Veterans, 1009 serving, a response rate of 26% from that group, 1767 completing the EQ5-D, 1458 who had deployed, 288 who had not and the 21 who did not provide deployment data. Of these, 247 were not used in the analysis due to missing values in one or more variables, leaving 1520 for analysis. A significantly higher proportion of Veterans reported ‘any problems’ rather than ‘no problems’ with four EQ-5D dimensions: mobility, self-care, usual activities and pain or discomfort, but no difference in anxiety or depression. Age, length of service, deployment, psychological flexibility and better sleep quality were associated with higher EQ-VAS scores; distress with lower EQ-VAS scores. Conclusion In this sample of New Zealand Veterans, psychological flexibility and good sleep are associated with better self-rated health, and distress and poor sleep with diminished health. These factors might be used as sentinel health indicators in assessing Veteran health status, and cognitive–behavioural therapy encompassing these domains may be useful in improving the health of New Zealand Veterans

Generic Preemption: Applying Conflict Preemption after Wyeth v. Levine

If a generic manufacturer does not have control over its safety warnings, can it comply with the obligations posed by state tort liability? State failure-to-warn actions evaluate whether a product manufacturer has met its obligation to warn consumers about known dangers associated with its product. In essence, if a manufacturer knows about a potentially dangerous outcome, it has a duty to warn its consumers. If the generic manufacturer can comply with a state duty to warn only by changing a label that the FDA will not allow it to change, it becomes impossible for the corporation to meet both requirements. This impossibility indicates that conflict preemption applies and the generic manufacturer ought not to be liable for claims arising under state tort law. This situation is distinct from branded pharmaceutical manufacturers who do have the ability to control and modify their safety labels. Part I begins by examining the doctrine of preemption, considering state tort liability and federal preemption theories. Part II reviews recent Supreme Court jurisprudence relevant to pharmaceutical preemption. Part III then looks at how generic drugs fit into the preemption landscape and concludes that preemption applies to generic drugs. Finally, Part IV evaluates the implications of preemption within the generic drug context

Refinement and Pattern Formation in Neural Circuits by the Interaction of Traveling Waves with Spike-Timing Dependent Plasticity

Traveling waves in the developing brain are a prominent source of highly correlated spiking activity that may instruct the refinement of neural circuits. A candidate mechanism for mediating such refinement is spike-timing dependent plasticity (STDP), which translates correlated activity patterns into changes in synaptic strength. To assess the potential of these phenomena to build useful structure in developing neural circuits, we examined the interaction of wave activity with STDP rules in simple, biologically plausible models of spiking neurons. We derive an expression for the synaptic strength dynamics showing that, by mapping the time dependence of STDP into spatial interactions, traveling waves can build periodic synaptic connectivity patterns into feedforward circuits with a broad class of experimentally observed STDP rules. The spatial scale of the connectivity patterns increases with wave speed and STDP time constants. We verify these results with simulations and demonstrate their robustness to likely sources of noise. We show how this pattern formation ability, which is analogous to solutions of reaction-diffusion systems that have been widely applied to biological pattern formation, can be harnessed to instruct the refinement of postsynaptic receptive fields. Our results hold for rich, complex wave patterns in two dimensions and over several orders of magnitude in wave speeds and STDP time constants, and they provide predictions that can be tested under existing experimental paradigms. Our model generalizes across brain areas and STDP rules, allowing broad application to the ubiquitous occurrence of traveling waves and to wave-like activity patterns induced by moving stimuli

Discovery and Expansion of Gene Modules by Seeking Isolated Groups in a Random Graph Process

BACKGROUND: A central problem in systems biology research is the identification and extension of biological modules-groups of genes or proteins participating in a common cellular process or physical complex. As a result, there is a persistent need for practical, principled methods to infer the modular organization of genes from genome-scale data. RESULTS: We introduce a novel approach for the identification of modules based on the persistence of isolated gene groups within an evolving graph process. First, the underlying genomic data is summarized in the form of ranked gene-gene relationships, thereby accommodating studies that quantify the relevant biological relationship directly or indirectly. Then, the observed gene-gene relationship ranks are viewed as the outcome of a random graph process and candidate modules are given by the identifiable subgraphs that arise during this process. An isolation index is computed for each module, which quantifies the statistical significance of its survival time. CONCLUSIONS: The Miso (module isolation) method predicts gene modules from genomic data and the associated isolation index provides a module-specific measure of confidence. Improving on existing alternative, such as graph clustering and the global pruning of dendrograms, this index offers two intuitively appealing features: (1) the score is module-specific; and (2) different choices of threshold correlate logically with the resulting performance, i.e. a stringent cutoff yields high quality predictions, but low sensitivity. Through the analysis of yeast phenotype data, the Miso method is shown to outperform existing alternatives, in terms of the specificity and sensitivity of its predictions

Design of a series visco-elastic actuator for multi-purpose rehabilitation haptic device

<p>Abstract</p> <p>Background</p> <p>Variable structure parallel mechanisms, actuated with low-cost motors with serially added elasticity (series elastic actuator - SEA), has considerable potential in rehabilitation robotics. However, reflected masses of a SEA and variable structure parallel mechanism linked with a compliant actuator result in a potentially unstable coupled mechanical oscillator, which has not been addressed in previous studies.</p> <p>Methods</p> <p>The aim of this paper was to investigate through simulation, experimentation and theoretical analysis the necessary conditions that guarantee stability and passivity of a haptic device (based on a variable structure parallel mechanism driven by SEA actuators) when in contact with a human. We have analyzed an equivalent mechanical system where a dissipative element, a mechanical damper was placed in parallel to a spring in SEA.</p> <p>Results</p> <p>The theoretical analysis yielded necessary conditions relating the damping coefficient, spring stiffness, both reflected masses, controller's gain and desired virtual impedance that needs to be fulfilled in order to obtain stable and passive behavior of the device when in contact with a human. The validity of the derived passivity conditions were confirmed in simulations and experimentally.</p> <p>Conclusions</p> <p>These results show that by properly designing variable structure parallel mechanisms actuated with SEA, versatile and affordable rehabilitation robotic devices can be conceived, which may facilitate their wide spread use in clinical and home environments.</p